Isothiocyano diphenylamines

ABSTRACT

ISOTHIOCYANO-DIPHENYLAMINES OF THE FORMULA   (R1,R2-PHENYL)-N(-R)-C6H3(-N=C=S)-R3   WHEREIN THE ORTHO POSITIONS, IN RINGS A AND B, RELATIVE TO AN -NH- BRIDGE ARE FREE FROM ISOTHIOCYANO SUBSTITUENTS, R REPRESENTS HYDROGEN, ALKYL OF AT MOST 3 CARBON ATOMS OR ALKENYL OF AT MOST 3 CARBON ATOMS, R1 AND R3 REPRESENT, INDEPENDENTLY OF EACH OTHER YDROGEN, MIDDLE HALOGEN, CYANO, HYDROXY, NITRO, CARBOXY, TRIFLUOROMETHYL, ALKYL, ALKENYL, ALKOXY, ALKENYLOXY, ALKYLTHIO, ALKENYLTHIO, EACH OF THE LATTER SIX GROUPS HAVING AT MOST 5 CARBON ATOMS, ALKANOYLAMINO, ALKANOYL, ALKANOYLOXY, ALKOXYCARBONYL, EACH OF THE FOUR LAST-MENTIONED GROUPS HAVING AT MOST 6 CARBON ATOMS, DIALKYLAMINO HAVING A TOTAL OF AT MOST 5 CARBON ATOMS, A GROUP   D-N(-R&#39;&#39;)2, OR A GROUP -X-D-N(-R&#39;&#39;)2   WHEREIN D IS ALKYLENE OF 2 OR 3 CARBON ATOMS, R&#39;&#39; REPRESENTS ALKYL OF 1 TO 3 CARBON ATOMS, THE SUM OF THE CARBON ATOMS OF D AND R&#39;&#39; NOT EXCEEDING 6, AND X REPRESENTS OXYGEN OR SULFUR AND R2 REPRESENTS HYDROGEN, HALOGEN, NITRO, ISOTHIOCYANO OR ALKYL OF AT MOST 5 CARBON ATOMS, AND WHEREIN AN ISOTHIOCYANO GROUP MUST BE IN M- OR P-POSITION TO ANY HYDROXY OR CARBOXY BEING A SUBSTITUENT OF A BENZENE RING OR TO THE -NR-BRIDGE WHEN R IS HYDROGEN, AND, WHEN R, R1 AND R3 ARE HYDROGEN ATOMS, THE GROUP -NCS AT RING B IS IN M- OR P-POSITION AND ANY ISOTHIOCYANO GROUP R2 IS IN M-POSITION, ARE DISCLOSED AS NOVEL ANTHELMINTIC AGENTS. THEIR PRODUCTION, THEIR USE IN THE CONTROL OF HELMINTHS AND COMPOSITIONS CONTAINING THEM ARE ALSO DISCLOSED.

United States Patent ABSTRACT OF THE DISCLOSURE Isothiocyano-diphenylamines of the formula NOS @-r@ R, R R:

wherein the ortho positions, in rings A and B, relative to an NH bridge are free from isothiocyano substituents, R represents hydrogen, alkyl of at most 3 carbon atoms or alkenyl of at most 3 carbon atoms, R and R represent, independently of each other hydrogen, middle halogen, cyano, hydroxy, nitro, carboxy, trifluoromethyl, alkyl, alkenyl, alkoxy, alkenyloxy, alkylthio, alkenylthio, each of the latter six groups having at most 5 carbon atoms, alkanoylamino, alkanoyl, alkanoyloxy, alkoxycarbonyl, each of the four last-mentioned groups having at most 6 carbon atoms, dialkylamino having a total of at most 5 carbon atoms, a group or a group X-D-N wherein D is alkylene of 2 or 3 carbon atoms, R' represents alkyl of 1 to 3 carbon atoms, the sum of the carbon atoms of D and R not exceeding 6, and X represents oxygen or sulfur and R represents hydrogen, halogen, nitro, isothiocyano or alkyl of at most 5 carbon atoms, and wherein an isothiocyano group must be in mor p-position to any hydroxy or carboxy being a substituent of a benzene ring or to the NR-bridge when R is hydrogen, and, when R, R and R are hydrogen atoms, the group NCS at ring B is in mor p-position and any isothiocyano group R is in m-position, are disclosed as novel anthelrnintic agents. Their production, their use in the control of helminths and compositions containing them are also disclosed.

DESCRIPTION OF THE INVENTION The present invention concerns new isothiocyano-diphenlyamines and processes for the production of these new compounds, as well as the use of the new compounds for the control of parasitic helminths.

Among endoparasites which occur in warm-blooded animals, helminths are those which cause the greatest damage. Thus animals attacked by them, for example, not only show retarded growth, but often injuries occur which can result in the death of the animals. It is, therefore, of great importance to develop agents which are suitable for combating helminths in all stages of their development and for preventing infestation by these parasites. Although there are a number of substances known having anthelmintic properties, they are often not wholly satisfactory, be it that their action is insufiicient when applied in toxicologically tolerable doses, or that when applied in therapeutcially efiective doses undesirable side effects appear, or that they show only a very specific range of action.

In the present description, the term helminths refers to nematodes, cestodes and trematodes, i.e. to worms which infest the gastrointestinal tract, the liver and other organs.

The novel anthelmintically active isothiocyano-diphenylamines correspond to the Formula I R1 N C S @tg i R; R R3 wherein the ortho positions, in rings A and B, relative to an NH-bridge are free from isothiocyano substituents, R represents hydrogen, alkyl of at most 3 carbon atoms or alkenyl of at most 3 carbon atoms, R and R represent, independently of each other hydrogen, middle halogen, cyano, hydroxy, nitro, carboxy, trifiuoromethyl, alkyl, alkenyl, alkoxy, alkenyloxy, alkylthio, alkenylthio, each of the latter six groups having at most 5 carbon atoms, alkanoylamino, alkanoyl, alkanoyloxy, alkoxycarbonyl, each of the four last-mentioned groups having at most 6 carbon atoms, dialkylamino having a total of at most 5 carbon atoms, a group wherein D is alkylene of 2 or 3 carbon atoms, R represents alkyl of 1 to 3 carbon atoms, the sum of the carbon atoms of D and R not exceeding 6, and X represents oxygen or sulfur, and R represents hydrogen, halogen, nitro, isothiocyano or alkyl of at most 5 carbon atoms, and wherein an isothiocyano group must be in mor p-position to any hydroxy or carboxy being a substituent of a benzene ring or to the NR-bridge when R is hydrogen, and when R, R and R are hydrogen atoms, the group NCS at ring B is in mor p-position and any isothiocyano group R is in m-position.

As alkyl and alkenyl radicals, R and R in the above formula are meant straight chain or branched chain radicals, for example the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl and pentyl radicals, as well as allyl, methallyl, propenyl, isopropenyl and butenyl radicals, and dialkylamino radicals R and R have, in straight chains, 1 to 5 and in branched chains 3 to 5 carbon atoms. Alkenyloxy radicals R and R have in straight chains 2 to 5 and in branched chains 3 to 5 carbon atoms.

As alkanoyl radicals R and R are for example the following: the formyl, acetyl, propionyl, butyryl, valeryl, isobutyryl and isovaleryl radicals. Such alkanoyl radicals preferably also form the alkanoyl radical of an alkanoylamino group. In an alkoxycarbonyl radical, the alkoxy moiety has at most 5 carbon atoms in a straight or branched chain. Halogen represents chlorine and bromine.

Compounds of the Formula I wherein R represents hydrogen R represents hydrogen, halogen, nitro, alkoxy of at most 5, in particular 1 or 2 carbon atoms or alkylthio with at most 5, in particular 1 or 2, carbon atom, R repwherein R represents hydrogen, halogen, nitro, amino or an alkyl radical with at most carbon atoms, R, R and R have the meanings given for Formula I,

and wherein a primary amino group being in mor p-position to hydroxy, carboxy or to the NR- bridge when R is hydrogen, and only in those cases where R, and/or R represent a substituent other than hydrogen the NH; group at ring B as well as any NH group R' can be in para-position to the -NR bridge when R is hydrogen, with (a) A thiocarbonic acid derivative of the formula:

Hal-gjJ-Y wherein alkyl S alkyl wherein alkyl represents a lower alkyl radical having at most 4 carbon atoms, and m represents the integer 1 or 2, or

(c) Pentathio-dipercarbonic acid-bis(trihalogenoalkyl) esters.

The process are preferably performed in the presence of solvents or diluents which are inert towards the reaction components.

For the process according to the invention, as thiocarbonic acid derivatives mentioned under (a), either thiophosgene, optionally in the presence of an acid-binding agent and at temperatures ranging between 0 and 75 C., or N,N-diethylthiocarbamoyl chloride at temperatures between 40 and 200 C. are used.

The thiocarbonyl group is introduced by known methods: reactions of amines with thiophosgene (a) are described in Houben-Weyl 4th ed., vol. 9, page 867 (1955); the use of acid-binding agents is described by O. E. Schultz in Arch. Pharm. 295, 146-151 (1962); the reaction of amines with N,N-diethylthiocarbamoyl chloride (at) is described in the Journal Org. Chem. 30, 2465 (1965), with bis-thiocarbamoyl sulfides (b) by F. H. Marquardt in Helv. Chim. Acta 49, 1716 (1966), and those with pentathio-dipercarbonic acid-bis-(trihalogenoalkyl) esters (c) by R. Gottfried in Angew. Chemie 78, 985 (1966).

The new isothiocyano-diphenylamines of Formula I, wherein R R and R have the meanings given for Formula I, with the exception that nitro, carboxy and trifiuoromethyl must be at a ring not bearing an amino group, are also obtained by reacting a diphenylamine of Formula II, in which R R' and R have the meanings given for Formula II with the exception that nitro, carboxy and trifluoromethyl must be at a ring not hearing an amino group.

(d) With ammonium thiocyanate in the presence of excess hydrogen chloride in a solvent which is inert to wards the reaction components, preferably in an aromatic hydrocarbon or halohydrocarbon;

(e) With benzoyl isothiocyanate into the corresponding thiourea and this is then decomposed by heating, in the presence of a solvent which is inert towards the reaction components, preferably in an aromatic hy rocarb n r 4 halohydrocarbon, or in the presence of acids or acid anhydrides;

(f) With carbon disulfide in the presence of an inorganic base .or a tertiary amine into the corresponding dithiocarbamic acid salts and then splitting off the mercapto moiety therefrom.

For the reactions mentioned under (d) and (e), chlorobenzene is preferably used as solvent, other suitable solvents are, however, also dichlorobenzene, toluene, xylenes, cumene, etc. Process (d) is performed according to British Pat. No. 1,099,768, by saturating the solution of the diphenylamine with hydrogen chloride gas, then adding the ammonium thiocyanate and refluxing for several hours under continual introduction of hydrogen chloride. The thermal decomposition of thioureas (e) is performed in the manner described by I. N. Baxter et al. in J. Chem. Soc. (1956), page 659 if. The thioureas are produced according to Org. Snythesis III 735 (1955). As inorganic bases for the production of dithiocarbamic acid salts (f), for example the hydroxides, oxides and carbonates of alkali metals and alkaline earth metals as well as ammonium hydroxide are used; as tertiary amines, for example, trialkyl amines, pyridine bases, etc., are used. The stripping oil? of the mercapto moiety can be performed oxidatively with metal salts (British Pat. No. 793,802; Dutch Pat. No. 81-, 326), e. g. with lead, copper, zinc or iron-(III) salts, iodine, alkali metal hypochlorites or chlorites, preferably those of potassium and sodium (French Pat. No. 1,311,855), furthermore, with suitable acid halides such as phosgene and phosphoroxy chloride [D. Martin et al., Chem. Ber. 98, 2425-2426 (1965)], as well as with elementary chlorine and ammonium sulfide (German specification open to public inspection No. 1,192,189) or Chloramine T (British Pat. No. 1,024,913).

New isothiocyano-diphenyl amines of the more specific Formula III:

( A- :1 NC S a R R5 R represents hydrogen or alkyl of at most 3 carbon atoms or alkenyl of at most 3 carbon atoms,

R represents alkyl of at most 5 carbon atoms or alkenyl radical of at most 5 carbon atoms, dialkylaminoalkyl of at most 6 carbon atoms,

Y represents oxygen or sulfur,

n represents zero or 1,

R represents hydrogen, isothiocyano, halogen, nitro, trifluoromethyl, alkyl of at most 5 carbon atoms or alkenyl of at most 5 carbon atoms,

R represents hydrogen, halogen, nitro, trifluoromethyl, alkyl of at most 5 carbon atoms or alkenyl of at most 5 carbon atoms, or the group Y--R wherein Y and R have the meanings given above,

II) wherein the NCS group at ring B and any isothiocyano group R being in mor p-position in case R represents hydrogen, and in those cases where n represents zero, R represents the group Y-R are obtained according to another modification of the process according to the invention by reacting an isothiocyano-diphenyl amine of Formula IV:

(HY 11 No S V) wherein and in those cases where n represents zero, R' represents the group -YH, and R and R are as defined above,

with a compound of Formula V:

wherein R, has the meanings given for Formula III, and Z represents chlorine, bromine or iodine,

RI N01 R; Rs (V1) wherein R R and R are as defined under Formula I, preferably in the presence of an acid binding agent and of a solvent inert towards the reactant, with a compound of Formula VII R-E (V wherein R has the meaning give above and E represents a halogen atom or an alkoxysulfonyloxyor arylsulfonyloxy-group and reducing by methods know per se the so obtained N-alkylor N-alkenyl-nitrodiphenylamine to the N-alkylor N-alkenyl-nitrodiphenylamines, for instance, not only by means of molecular hydrogen, but also by means of nascent hydrogen, formed, e.g. in a solution or suspension of the nitro-diphenylamine. Moreover, the reaction may be performed also by means of hydrogenation catalysts, such as e.g. Raney-nickel, and Raney-cobalt. Nitro-diphenylamines of Formula VI are in part known and in part new compounds. As far as they are new, they may be prepared according to Houben-Weyl ll/I, page 242 or F. Ullmann, Ber. 41, 3744-3755 (1908).

The novel isothiocyano-diphenylamines of Formula I wherein one of the symbols R and R represent a tertiary amino group can be converted into the corresponding salts with acids that are non-toxic for human and animal organisms. Suitable acids are inorganic and organic acids such as, for example, hydrohalic acid, sulfuric acid, phosphoric acids, acetic acid, amino-acetic acid, butyric acid, lauric acid, stearic acid, oxalic acid, adipic acid, maleic acid, tartaric acid, lactic acid, methane sulfonic acid and ptoluene sulfonic acid, or for the production of quaternary salts and they can be converted with the usual quaternizing agents such as alkyl halides, dialkyl sulfates, toluene sulfonic acid esters, etc., into the corresponding quaternary ammonium salts. If the anion of the quaternary salt is toxic .for the animal organism, it can be exchanged for a non-toxic anion by reacting with a non-toxic acid.

The amines serving as starting materials can be employed in the form of the free bases and also as acid addition salts, especially those from mineral acids. Examples of suitable inert, organic solvents that can be employed in the process according to the invention are the following: aliphatic or aromatic hydrocarbons, aliphatic and aromatic halohydrocarbons, ether and ethertype compounds, water or mixtures of such solvents with water.

The isothiocyano-diphenylamines according to the invention, and their salts, including the quaternary salts, possess decided anthelmintic properties. The new active substances are especially suited for combating parasitic nematodes: such as ascaridae, trichostrongylidae, stro'ngylidae, ancylostomatidae;

cestodes: such as taeniidae, anoplocephalidae;

trematodes: such as fasciolidae;

in pets and domestic animals such as cattle, sheep, goats, horses, pigs, cats, dogs and poultry.

The active substances can be administered to helminthinfested animals or to animals to be protected against helminths in the form of therapeutical preparations either as one single dose of repeatedly, the single dosage, depending on the type of animal, preferably between 25 and 1000 mg. per kg. bodyweight.

In some cases better results are obtained or the total amount required for a cure can be decreased by protracted administration. The concentration in which the active substances in the form of such agents are added, e.g. to feeds or liquids given to animals are between 0.05 and 1% by weight.

The novel isothiocyano-diphenylamines and their salts which are non-toxic for the organism, can be administered to the animals perorally or via the abomasum in the form of solutions, emulsions, suspensions (drenches), powders, tablets, boluses and capsules.

To prepare the forms of application listed above, conventional solid carriers can be used such as kaolin, talcum, bentonite, sodium chloride, calcium phosphate, carbohydrates, cellulose powder, cottonseed meal, carbowaxes, gelatins, or liquids such as water, if desired with the addition of surface active substances such as ionic or non-ionic dispersing agents, and also oils and other solvents which are well tolerated by the animal organism. When the anthelmintic agents are in the form of feed concentrates, carriers which can be used are, for example, formulated foods, grain feeds or protein concentrates. Such feed concentrates can also contain, in addition to the active substances, other additives, e.g. vitamins, antibiotic, chemotherapeutic, bacteriostatic, fungistatic and coccidiostatic substances, hormone preparations, substances having an anabolic activity or other substances which promote growth, influence the quality of the meat of fat stock animals or are useful to the animal organism in other ways.

Some tests to determine the anthelmintic activity of the new isothiocyano-diphenylamines of the general Formula I are described below.

Determination of the anthelmintic action on chickens infested with Ascaridia galli 1 to 3 day-old chicks were artificially infested with eggs of Ascariaia galli. Groups of 5 chicks each were used for each test. 4 to 5 weeks after infestation, the active substances were administered to the animals in a single dose per day on 3 consecutive days. Infested chickens that had not been treated served as controls.

Evaluation The number of Ascaridia galli eliminated by each test group during 5 days after the first administration of the active substance was determined daily and in addition the number of worms still found in the intestine after dissection on the 5th day. Furthermore, the number of chickens free from worms was determined.

Number of Ascaridia 94111: from 5 chickens Eliminated during the test Daily dosage, In per- Number mgJkg. cent of Found of worm- General body Absolute the total at disfree con- Aetive substance weight number number section chickens dition 4-chl0ro-2 -carboxy-'dsothioeyanodiphenyl amine 500 41 100 Good 3-methyht-1sothiocyane-diphenylamine .4 500 358 100 0 5 Do.

4-nitro-4-isothiocyano-diphenylamine 500 80 100 0 5 D0. 4-methyl-4-isothiocyano-diphenylamine. 500 72 100 0 5 Do. 4-tert-butyl4'-isothiocJyano-diphenylamine- 500 65 100 0 5 Do. 4-methyl-3-isothiocyano-iphenylamine 500 199 100 0 5 Do. 4-hydroxy-4-isothiocyano-diphenylamine 500 119 86 19 3 D0. 4-0hlore-4-isothiocyano-diphenylamine. 500 37 100 0 5 D0. 3-isothioeyano-diphenylamine 500 169 100 0 5 Do.

A-methoxy 4-isothiocyano-diphenylannne 500 86 100 0 5 Do.

4-methylthio-i-isothiocyano-diphenylamine. 750 133 100 0 5 Do.

N-allyl-4-chloro-4-isothiocyano-diphenylamine 750 211 98 4 4 D0.

3,4-dimethyl4-isothiocyano-diphenylamine 750 105 100 0 5 Do.

3-trifluorornethyl-3'-isothioeyano-diphenylamine. 170 168 98 2 3 Do. -bromo4'-isothioeyano-diphenylamine 750 164 100 0 5 Do. 3-nitro4'-isothioeyano-diphenylamine. 600 104 100 0 5 D 3,4-diisottiiocyanodiphenylamine 750 137 100 0 5 D Tests on mice infested with Hymenolepis nana TABLEContlnued The active substances, in the form of a suspension, were D n administered via an esophagal syringe to white mice which a Infestation Infestation of had been infested with Hymenolepis nana. Five animals s f the tesz the colllstrol were used for each test. The active substances were acl- Active substance weight 'giiifi aggi g; ministered once a day to each test ammal on 3 consecu- 3,4 -b1s-1sothioeyanotlve days. The animals were then killed and dissected 0n diphenylamine 750 (HHHHH) the 8th day after the beginning of the treatment. t i w isothioc ano-di hen 'lamme 7'0 -(H -O The results were evaluated after dissection of the test N allyl-4-r nethox-4'- 3 a 0'0 34 5-6 9 animals by counting the number of tape worms in the intestines. Untreated mice which had been infested in the diphenylamine 50 W same way and at the same time served as controls diphenylamine 250 0-0-0-0-0 6-12-14-16-22 The agents were tolerated by the mice without any sym- 3,4-dimethyl-4dsothiocyanot ms dlphenylarn ine 750 0-0-0-2-1 23567 4-methoxy-3asothiocyanodiphenylamine 750 0-0-0-0-0 14-18-21-27-33 Daily dosage, Infestation Infestation of mglkdg. eithgjtes; the eoritro'l2 0y amm sa animasa Active Substance weight dissection dissection 40 Tests on rats infested with Fasczola hepatzca 3-lgielilyl-4i-istligliocyano- 500 0mm WQ 1 White laboratory rats are infested with liver fiukes g i,g gg (Fasczola h epanca). On completion of the prepatency g g g gg fi 750 period, the infestation of the rats by liver flnkes is deterdilg enylnmjrgi 750 (HHHH) 2241-5-15-21 i ed by three separate analyses of the faeces.

4 fif t g 400 0 0 8 0 23 q 5 d S rf eatcllll test 2 to 1 lIziffisted lljltil are treateg once -e oro--iso 'oeyanoa y or ree consecutive ays wit t e active sn stance di hen lemine 750 0-0-0-0-0 28-191G11-13 i zfimgmmgthoxyatisot which is applled via an esophagal syringe 111 the form of i g fifiggifigg W a suspension. From the third to the fifth week after ad- 'difzllilerig kluarnlj nimifii o 0-0-0-0-0 4-6247 ministration of the active substance, the faeces are anagg g g gj jfifj 750 041W lyzed once a week to determine Whether they contain g gg 'ggg gw 500 & any eggs of liver flukes. At the end of the fifth week of t tm ggh'g. the test, the test animals are killed and examined for diplleflylfl-mine 750 the resence, of liver flukes,

4-acetarnido-3-isothiocyanop diphenylamine 750 0-0-0-0-0-0 3-5-44 Daily Examination of faeces for Number dosage, elimination of eggs 3 times of liver of body Before After after discon- A ti substance weight medication medication section dition ZA-dinitro-4-isothioeyano-diphenylarnine 200 Posi ive.-- Negative..- 0-0 Good 3-methyl-4'4s0thiocyano-diphenyiamine 50 (1 Do. 4-methnxy-2'-earboxy-5'-isothioeyano-diphenylannne Do. 4-nitro-4-isothioeyano-dipheny D0. i-acetylamino4'-isothioeyano-diphenylamne Do. a-methyl-4'4sothioeyano-diphenylamine Do. 2-0arboxy-3-isothioeyano-dipheny1am ne Do. 2-earboxy-44sothioeyano-diphenylamme Do. e-chloro-4-isothioeyano-diphenylamine Do, 2-earboxy-3'-isothiocyano-diphenylamine D0. 2-carbomethoxy-4-3'-isothiocyano-d1phenylamme Do. 4-methyltliio-4-isothiocyano-diphenylamino. Do. N-a1lyl-4eh1oro-4'-isothiocyano-diphenylarmne- Do. N-allyli-methyl-4'-isothioeyano-diphenylamine Do. N-n-propyl-B-methoxy-tdsothioeyano-diphenylarnlne Do. N-aliyl--methylthio-4'-isothiecyano-diphenylamme D0. -isothioeyanodiphenylamine Do. 3-chloro-4'-isothioeyano-diphenylannne. Do. B-nifire-4'4sothioeyano-diphenylam ne Do. Mlimethylamino-dsothiocyano-diphenylamine 1130.

3,4-dimethyl44sothiocyano-diphenylamine Tests on mice infested with mouse oxyuridae The active substance was administered via an esophagal syringe in the form of a suspension to white mice which had been infested with mouse oxyuridae. animals were lution is decanted, and the residue is extracted 3 more times with 100 parts by volume each of ether. The combined ether extracts are concentrated and the remaining 4-methyl-4'-isothiocyano-diphenylamine distills at 181- 183/0.02 torr. Melting point of the distilled product:

used for each test. The active substances were adminis- 5 O 64-66 tered to each test animal once daily for three consecu- EXAMPLE 4 tive days. The animals were then killed on the 8th day after treatment had begun, and dissected. 44 parts of thiophosgene in 50 parts by volume of The results were evaluated after dissection of the test chloroform are added dropwise to a solution of 73 parts animals by counting the number of mouse oxyuridae in 10 of 4-methylthio-4-aminodiphenylamine in 300 parts by the intestines. Untreated mice which had been infested volume of chloroform and 63.5 parts of sodium bicarbonin the same manner served as controls. ate in 1000 parts by volume of water. After completion The agents were tolerated by the mice without any of the addition, stirring is continued for 6 hours at room symptoms. temperature, the layers are separated, the chloroform Daily dosage, Length of Infestation mg.[kg. adminisof the 5 test Infestation of the body tration animals at control animals at Active substance weight in days dissection dissection 3-n1ethyl-4-isothiocyanodiphenylamine- 500 3 0-0-0-0-0 5/Ll7/L20/l0/Ll8/Ll 4-nitro-4-isothiocyano-diphenylarnine. 750 3 0-00-0-0 9/Ll-25/Ll-0/L-0/L-4/Ll 4-rnethyl-4-isothioeyano-diphenylamine 750 3 0-0-0-0-0 2-4 ()3/L-12/L 4-tert-butyl4-isothloeyano-diphenylami 759 3 24'03/L12/L 4-methyl-3-isothioeyano-diphenylamine. 750 3 0-0-0-0-0 24=O3/L12/L 4-chloro-4'-isothiocyano-diphenylamine... 750 3 0 000-0 12/Ll-4/l-0-9-4/L 4methoxy-4-isothioeyano-diphenylamine 750 1 04)0-O-0 4-7-12-10-24 2-carbomethoxy-3-isothiocyano-diphenylamine 750 3 0-043-0-0 4/L4/Ll5/Ll7/Ll 4/Ll 4-methylthio-3-isothiocyano-diphenylamine 750 3 0-0-0-0-0 82/1-36/1-45/1-5/l-5/L1 4-methylthio-4-isothiocyano-diphenylamine 750 3 0-0-0-0-0 82/l-36/1-45/l-5/l-4/L1 3-chloro4-isothioeyano-dipheuylamine.. 500 3 0-0-0-0-0 0-0lL-2-1-1 3-nitro-4'-isothioeyano-diphenylamine. 750 3 0 3/Ll3/l08/1 4-acetamido-3-isothiocyano-diphenylamine.- 750 3 02L30-0 3/Ll-3/l-0-8/l 3,4-diisothiocyano-diphenylamine 750 3 0-0-0-2L-O 3/Ll-2/l-0-9/l N-n-propylt-methoxy-4-isothiocyano-diphenylamine. 750 3 0 4/Ir4/Ll-5/l-7ILl-4IL1 N-allylmethoxy4-isothiocyano-diphenylamine 750 3 0-0-0-0-0 4/L4/Ll5/Ll7/Ll-4/Ll N-allyl-4-chloro-4-isothioeyano-diphenylamine. 750 3 0O0010L 4/L4/Ll5/Ll7/Ll4/Ll N-n-propyl-3-methoxy-4-isothiocyano-diphenylamin 750 3 0-0-0-(HL l5/Ll-20/Ll-28/Ll-60l-40 irethyl'y-isothiocyano-diphenylamine 250 3 (HHHH) /Ll-20/L-28/Ll-60/L-40 3,4dimethyl-4'-isothiocyano-diphenylamine. 750 3 00000 15/Ll-20/L-28/Ll-60/b40 4-allyloxy-4-isothioeyano-diphenylamine 750 3 0000-0 51lLl-20/L-28/Ll-60/L-40 B-trifluoromethyl-4-ehloro-4'-isothiocyano-diphenylamine.. 750 3 8-10-11-12-13/1 4-bromo-4-isothiocyano-diphenylannu e 750 3 00000 4/L1-5/L1-7/Ll-12/Ll-24/Ll 4-rnethoxy-3-isothiocyano-diphenylamine 750 3 (HHHH) 3/Ir12/L15/L-16/Ll28/Ll NoTE.-L=presenee of old larvae; l=presenee of young larvae.

The following examples illustrate the process accordsolution is dried over magnesium sulfate, filtered and coning to the invention. Where not stated otherwise, parts centratede reslfiue is dissolved in alcohol, n he 4- are expressed by weight. The temperatures are given in f Y y q p y i degrees centigrade 40 is precipitated by the addition of water. Yield: 65 parts.

EXAMPLE 1 EXAMPLE 5 A solution of 16.1 parts of 4-chloro-4'-aminodiphenyl- Parts of thiPh9sgene in 250 Parts by volume of amine in 100 parts by volume of dioxane is added dropgg i ii zq ffi z i g i i z wise to an emulsion of 9.6 parts of thiophosgene in 100 p S oxy- 1p any amme an 4 It b volum of ice water and Stirred f0 14 hours at parts of sodium bicarbonate in 200 parts by volume of P 5 Y 5 Th lt t h d ice water. After completion of the addition, stirring is room tempera e K e 5 continued for 8 hours at room temperature, the layers are well wlth Wa and after dfylng 1n vacuo 1S recryst i then separated, the organic phase is dried with calcium from ether/WHORE? ethef- 14 Parts chloride, filtered and concentrated. The residue is rethIOCYaIIO-dIPhBIIWamIIIG, i are bta111edcrystallized from toluene. 16.8 parts of 4-hydroxy-4'-iso- EXAMPLE 2 thiocyano-drphenylamine, M.P. l18l20, are obtained. 12.8 parts thereof are refluxed with 7.5 parts of potas- SOIHUOH 0f 19.8 Parts Of y f P sium carbonate in 40 parts by volume of acetone for 30 amine 1n 0 parts y volume of ether 18 added dropwise minutes with stirring; then 15.2 parts of allyl bromide to an emulsion of 12.6 parts of thiophosgene in 150 are added dropwise with cooling. After refluxing for 18 parts by volume of ice Water. After stirring for 8 hours hours, the reaction mixture is filtered, the filtrate is comat room temperature, the layers are separated, the orpletely concentrated, and the residue is recrystallized ganic phase is dried over potassium carbonate, filtered, from ether/petroleum ether to which animal charcoal concentrated, and the oil remaining is distilled in high j been f 11 Parts Y Q Y- Y vacuum. 11 parts of 3-methyl-4-isothiocyanodiphenyldlphenylamlnei 62-64 ,afe Obtainedamine, B.P. 169 173/ 0.002 torr, distill. EXAMPLE 6 EXAMPLE 3 7.4 parts of benzoyl chloride are added dropwise to a I solution of 4 parts of ammonium thiocyanate in 20 parts At -10", first 69 parts by volume of absolute triethylby volume of acetone. The mixture is refluxed and, while amine and then 9.7 parts by volume of carbon dioxide hot, treated with a solution of 11.5 parts of 4'-amino-4- are added dropwise, in such a manner that the internal methylthio-diphenylamine in 20 Parts y Volume of temperature does not exceed 0, to 32 parts of 4-methylf The reaction mixture is then Poured with Stirring 4'-aminodiphenylamine in 80 parts by volume of b l t Into 300 parts by volume of water, and treated with 150 ether parts by volume of 30% aqueous sodium hydroxide solu- After stirring for 18 hours at room temperature, 15.1 F andrthen rfifiuxed Afterfhe has 9 it parts y volume of p p y chloride in 18 parts y s neutra ized w1th hydrocl 1lonc acid, whlle cooling with ice, and the resulting precipitate is removed by suction. volume of absolute ether are added dropwise. (Internal The resulting 1 N (4, methy1thiopheny1) 4 amino phenyl i P p t0 tlme 0f addltlofl! 45 Stirring thiourea is dried and then refluxed for 10 hours in 100 is then continued for another 18 hours, the ethereal soparts by volume of chlorobenzene. The solvent is then 1 I removed by distillation and the residue is recrystallized from ethanol/water. The 4' isothiocyano-4-methyl-thiodiphenylamine has a melting point of 87-91". The mixed melting point with the compound obtained according to Example 4 shows no depression.

EXAMPLE 7 (a) 17.7 parts of 4 nitro-4-aminodiphenylamine in 200 parts by volume of ice water are treated with 9.7 parts of thiophosgene and stirred for 12 hours at room temperature. The resulting dark yellow precipitate is separated by filtration, dried in vacuum at 70 and recrystallized from acetone. 11.7 parts of 4-nitro-4'-isothiocyano-diphenylamine, M.P. 204206, are obtained.

(b) A suspension of 29.9 parts of 4-nitro-4'-aminodiphenylamine and 30.7 parts of bis-diethyl-thiocarbamoyl disulfide (tetraethyl thiouramdisulfide) in 500 parts by volume of chlorobenzene is saturated with hydrogen chloride gas at room temperature, while excluding atmospheric moisture; then it is stirred for 4 hours at reflux, filtered hot, the separated Warm organic layer is extracted with warm water, then dried over calcium chloride, filtered and concentrated. The crystalline residue is recrystallized from acetone/toluene to which animal charcoal has been added, whereby 10 parts of 4-nitro-4'-isothiocyano-diphenylamine, M.P. 202-205, are obtained. The mixed melting point with a sample of the substance obtained according to (a) shows no depression.

11.45 parts of 4-nitro-4-aminodiphenylamine and 7.95 parts of N,N-diethyl-thiocarbamoyl chloride are refluxed for 6.5 hours with 150 parts by volume of chlorobenzene. After removal of the solvent by distillation, the crystalline residue is dispersed in ethyl acetate/water, the layers are separated, the organic extract is dried over potassium carbonate, filtered and concentrated. The crystalline residue which remains is recrystallized according to Example 6(b) from acetone/toluene, whereby 5.1 parts of 4-nitro-4'-isothiocyano-diphenylamine having identical melting point and mixed melting point, are obtained.

(d) A solution of 11.5 parts of 4-nitro-4'-amino-diphenylamine in 100 parts by volume of chlorobenzene (anhydrous) is saturated with dry hydrogen chloride gas, then treated with 5 parts of ammonium thiocyanate and refluxed for 6 hours with continual introduction of hydrogen chloride gas. The undissolved portions are removed by filtration and the filtrate is concentrated to dryness in vacuum. The crystalline residue is recrystallized from acetone/toluene. The 4 nitro-4'-isothiocyano-diphenylamine, M.P. 204-206, is obtained; the mixed melting point with the substance obtained according to (a) shows no depression.

EXAMPLE 8 46 parts of 4-methoxy-4'-nitro-diphenylamine are refiuxed for minutes while stirring with 40 parts of finely pulverized potassium hydroxide in 400 parts by volume of acetone. A solution of 26.6 parts of allyl bromide in parts by volume of acetone is then carefully added dropwise at room temperature. Then the mixture is refluxed for 90 minutes while stirring and subsequently concentrated by evaporation. The residue is digested with water, filtered and, after drying, recrystallized from ethyl acetate/petroleum ether. 55 parts of N-allyl-4-methoxy- '-nitrodiphenylamine, M.P. 8l82, are obtained, which are reduced in dioxane with Raney nickel to N-n-propyl- 4-methoxy- '-amino-diphenylamine.

13 parts of the latter product in 200 parts by volume of ether are added dropwise to an emulsion of 6.5 parts of thiophosgene in 100 parts by volume of ice water. After completion of the addition, the mixture is stirred for 8 hours at room temperature. The organic phase is separated, dried over potassium carbonate, filtered, concentrated by evaporation, and the remaining oil is distilled under high vacuum. The resulting N-n-propyl-4-methoxy- 4'-isothiocyano-diphenylamine has a boiling point of 185- 188/0.1 torr.

12 EXAMPLE 9 23 parts of 4-methoxy-4'-nitro-diphenylamine are retfiuxed for 15 minutes while stirring with 20 parts of finely pulverized potassium hydroxide in 200 parts by Volume of acetone. 30 parts by volume of dimethyl sulfate are carefully added dropwise at room temperature, and the reaction mixture is refluxed for minutes while stirring and then concentrated by evaporation. The residual N- methyl-4-methoxy-4'-nitro-diphenylamine, which after recrystallization has a melting point of -126 is reduced In dioxane with Raney nickel to N-methyl-4-methoxy-4'- amino-diphenylamine, M.P. 76-79. 11 parts of the latter In 200 parts by volume of ether are added dropwise to an emulsion of 6.5 parts of thiophosgene in 100 parts by volume of ice Water. After completion of the addition, the mlxture is stirred for 8 hours at room temperature. The organic phase is separated, dried over potassium carbonate, filtered and concentrated by evaporation. The residual N methyl-4-methoxy-4'-isothiocyano-diphenylamine has, after recrystallization from benzene/ petroleum ether a melting point of 73-75 The following isothiocyano-diphenylamines of the Formula I are also produced according to the preceding examples:

TABLE Melting point or boiling point in 0., refrac- No. Compound tlou indices 10...- 3-ehlor04-isothiocyano-diphenylamine 86 11- 4-methyl-3-isothiocyano-diphenylarnine. RSI-163 12 4-bert-butyl-4dsothiocyano-diphenylamine.- 80-82" 13---- 2-nitro-4-is0thiocyano-diphenylamine 158-159 14.... 3-nitr0-4-isothiocyano-diphenylamine- 117 15.... 4-nitro-3-isothiocyano-diphenylamine-.- -142 16 2,4-dinitro-4isothioeyano-diphenylamine. 134-136 17 2,4-diuitro-3'-isothlocyano-diphenylamine 147 18. 4-methy1-4-nitro-3-isothiocyano-diphenylamine- 1158- 19-.-- 4-methylthto-3-lsothiocyauo-diphenylamine.-. 180-185", 0. 005 20- 2-carboxy-F-isothioeyano-diphenylamlne.-.. 196-197" 21 2-e arb0xy-3-isothiocyano-diphenylamine- 183-185 22...- 2-earboxv-5-isothlocyano-diphenylamine 201-203" 23- 4-chlaro-2-carboxy-4-isothiocyano-diphenyl- 220-222 am [18. 24 4-metihoxy-2-carb0xy-3-lsothlo cyano-diphenyl- 198-203 am no. 25- 4-metihoxy-2carb0xy-4-isothiocyano-dtphenyl- 183-185 am He. 26- 4-acetylamino-4-isothioeyano-dlphenylamlne--- fi l-165 27- 4-ncetylamin0-3'-is0thi0cyano-diphenylamine.- 152-155 28- 2-earbomethoxy-4'4sothiocyano-diphenylamine-. 95-98 29- 2-carbome thoxy-3-isothiooyano-diphonylamine.. 45-47 30.-.- 3,4'-diisotlnocyano-dlphenylamlne 108-111 31 4-dimethylamino-4dsothioeyano-diphenyl- 115-120 amine. 32-- 3-trifiuoromethyl-34sothlo cyano-diphenyl- 156-160/ 0. 2

amine. 33- 4-trimethyl ammonio-4'-is0thiocyano-diphenyl- 186-189 amineiodide. 34- 3-tritluoromethyl-4-chloro-4dsothio eyano-di- 87-92 phenylamine. 35--.- 3,'1-dimethyl-4'-isothlocyano-dtphenylamine--.-- 92-93 36- 4-hydroxy-t-isothiocyano-diphenylamine. 118-120 37. 3-isothioeyano-diphenylamine 212/ 0. 1 38.... -isothioeyano-diphenylamine 73-74 39-... 4-meth0xy-4'-isothiocyano-diphenylamine 55-57 40- 4-xnetih0xy-2earb0xy-5-isothiocyano-diphenyl- 198-203 am no. 41 4-bromo-4-isothiocyano-diphenylamlne 111-114 42.--- 4-valeryl-t'-isothioeyano-diphenylaminc. 132-135 43 4-eyan0-4-isothloeyauo-diphenylamine- 185-186" t-dimethylaminoethoxy4-isothioeyano-di- 117-120 phenylamine. 45- 3-trifi uoromethylt'dsothiocyano-dlphenyl- 77-7 9' amine. 46. N-allyl-4-chlor0-l'dsothio cyano-diphenylamine. 179-18l 47- N-allyl4-methyl-4dsothioeyano-diphenyln1) 1.6742

amine. 48- N-rggropyl-B-methoxy-Q-isothlocyano-dlphenyl- Oil a me. 49. N-allyl-d-methylthio-4'-isothiocyano-dlphenyl- 0. 001

31111116. 50- N-allyl-4-methoxy-ddsothiccyano-dlphenylmy" 1.6571

amine. 51- N-methylt-methoxyl-isothiooyano-diphenyl- 73-78" 31111118. 52- N-n-propy1-4-methoxy-4-isothio'cyano-diphenyl- 185-18870. 1

EJ111116- 53..-. 4-methylthi0-3-isothlocyano-diphenylamine.-... ISO-185] 0.005 54. 3-methoxy-4'-isothiocyano-diphenylamine- 63-65" 55- 4-methoxy-3-isothiocyano-diphenylamine- 59-61 56- -ethyl-4'-is0thiocyan0-diphenylamine -182/ 0. 1 57- 2-carbopropoxy-3'-isothiocyano-diphenylamlne- Oil 58.--. 4-acetoxy-4-isothiocyano-diphenylamiue loo-164 59- 4-diethylaminoethoxy-y-isothiocyano-diphenyl- 169-173 amine. See footnote at and of table.

TABLECont1nued Melting point, or boiling point in (3., refrac- No. Compound tion lndices 60 4-n-amyl-4-lsothlocyano-dlphenylamlne 62- 4-allylthio-4-lsothlo cyano-diphenylamine 63- 4-(2-dimethylaminoethyl)-4-isothiocyanodiphenylnmine.

64- 4-(3 -di.methylaminopropyl) 4-lsothi0eyano diphenylamine. 65 4-dlmethylarnino-4-lsothlocyano-diphenylamlne 1 Torr.

The following non limitative examples are given for the production of forms of application of anthelmintically effective veterinary-medical preparations and feed additives. Parts are given therein by weight.

EXAMPLE 73 A dispersable powder is produced by thoroughly milling and mixing 50 parts of 4-nitro-4-isothiocyano-diphenylamine, 1 part of a condensation product obtained from ethylene oxide and the condensation product of propylene oxide and propylene glycol having a molecular weight of about 2000 (e.g. the commercially available Pluronic L 61), 5 parts of the ammonium salt of a sulfonated naphthalene sulfonic acid-phenol-formaldehyde condensate (e.g. the commercially available Irgatan AG 1") and 44 parts of kaolin.

A dispersable powder is also obtained when 50 parts of 4-chloro-4'-isothiocyano-diphenylamine, 1 part of a condensation product obtained from ethylene oxide and the condensation product of propylene oxide and propylene glycol having a molecular weight of about 8000 (e.g. the commercially available Pluronic F 68), 0.5 part of sodium lignin sulfonate and 48.5 parts of sodium aluminium silicate are used.

These dispersable powders can be mixed with liquid or pulpy feeds for administration to pets and domestic animals.

EXAMPLE 74 2 parts of 4-nitro-4'-isothiocyano-diphenylamine are thoroughly mixed with 2 parts of a condensation product obtained from ethylene oxide and the condensation product of propylene oxide and propylene glycol (e.g. the commercially available Pluronic L-64) and 96 parts of glycolmonoethyl ether to form an emulsion concentrate which can be dispersed in any concentration desired, e.g. in water or milk for administration to pets and domestic animals.

EXAMPLE 75 40 parts of 4-methyl-4'-isothiocyano-diphenylamine are thoroughly mixed with 2.5 parts of sodium lignin sulfonate, 0.3 parts of sodium benzoate, parts of glycerol and 47.2 parts of distilled Water to form a paste,

14 which can be mixed with liquid or pulpy feeds Ior administration to pets and domestic animals.

EXAMPLE 76 35 parts of 4-nitro-4-isothioeyano-diphenylamine are thoroughly mixed with 15 parts of molasses, 5 parts of pulverised liquorice, 25 parts of pulverised hay and 20 parts of ground bran. The obtained mixture is shaped by means of a press into briquets which can be added to the feed.

In the above Examples 73 to 76 the active substance of Formula I can be replaced by any of the compounds disclosed in the Examples 1 to 9 or in the table.

We claim:

1. A compound of the formula wherein R is nitro, chlorine or methyl.

2. A compound as defined in claim 1 which is 4-nitro- 4'-isothiocyano-diphenylamine.

3. A compound as defined in claim 1 which is 4- methyl-4'-isothiocyano-diphenylamine.

4. A compound as defined in claim 1 which is 4-chloro- 4'-isothiocyano-diphenylamine.

References Cited UNITED STATES PATENTS 3,558,784 1/1971 Paltauf et a1. 260454 3,366,538 1/1968 Werres et a] 424302 3,471,576 10/1969 Klesper et al. 424-337 3,285,730 11/1966 Weis et a1 260454 3,098,006 7/ 1963 Soder et al. 424-302 2,059,800 11/1936 Laska et al. 260576 2,572,067 10/1951 Smith 260576 3,248,427 4/ 1966 Greenfield 260576 3,277,175 10/1966 Clemens, Jr. 260576 3,367,957 2/ 1968 Newallis et al. 260454 FOREIGN PATENTS 793,802 4/ 1958 Great Britain 260454 1,024,913 4/ 1966 Great Britain 260454 1,099,768 1/1968 Great Britain 260454 OTHER REFERENCES Cymerm an-Cnaig et al.: Some Diphenylamines etc. (1960), CA 55, pp. 1903243 (19 61).

Anthoni et al.: N-isothiocyanatoamines etc. (1967), CA 67, No. 99764 v. (1967).

Banchetti.: Res. on Anthelmintic Drugs, (1953), CA 50, p. 15949 (1956).

Van Esch.: Carcinogenic Action of Various Diphenylamine etc. (1960), CA 54, p. 21451 (1960).

Mackie et al.: Anthelmintic Activity etc. (1955), J. Pharm. & PharmacoL, vol. 7, p. 616 (1955).

LEWIS GOTTS, Primary Examiner G. HOLLRAH, Assistant Examiner US. Cl. X.R. 424-302 UNITED STATES TPATENT OFFICE CERTEFKATE 0F CURRECTION Patent No. 3,755,406 J Dated August 28, 1973 Inventm-(s) Paul Brenneisen, Jean-Jacques Gallay and Alfred Margot It is certified that error appears in the above--identified patent and that said Letters Patent are hereby corrected as shown below:

Heading in column 1: Between the line beginning "No Drawing" and the line beginning "lnt. Cl.", insert v Claims priority, application Switzerland, July 12, 1968 Signed and sealed this 12th day of March 197M.

(SEAL) Attest: 7 EDWARD M.FLETCHER, JR., (3. MARSHALL DANN Attesting Officer Commissioner of Patents FORM PO-105O (10-69) USCOMM-DC Basis-ps9 v U.S. GOVERNMENY PIINYING OFF CE 1959 0-366-334 t 

